The present invention provides numerous novel metabolites and prodrug formulations of 8-[4-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]butyl]-8-azaspiro[4.5]deca ne-7,9-dione (tiospirone) which are particularly useful in the treatment of psychotic disorders. In particular, the present invention includes substituted derivatives of the title compound and methods for their preparation such that one preferred group of compounds have the general Formula (I); ##STR2##
wherein R.sup.1 is selected from the group consisting of hydrogen, hydroxyl, lower (C.sub.1 -C.sub.4) alkoxy, higher (C.sub.9 -C.sub.17) acyloxy and oxo;
R.sup.2 is selected from hydrogen, methyl, hydroxyl, lower (C.sub.1 -C.sub.4) alkoxy, higher (C.sub.9 -C.sub.17) acyloxy and acetoxy;
R.sup.3 is hydrogen, hydroxyl, and methoxy;
R.sup.4 is hydrogen, methyl and oxo, with the proviso that R.sup.1 and R.sup.2 cannot be acyloxy simultaneously and the solid and dotted lines refer to either a double covalent bond or a single covalent bond with another hydrogen atom covalently bonded to the carbon terminus end;
X is selected from the group consisting of S, SO, and SO.sub.2, with the proviso that X cannot be S or SO when R.sup.1, R.sup.2, R.sup.3 and R.sup.4, are all hydrogen; and the pharmaceutically acceptable salts and solvates thereof.
Tiospirone is an antipsychotic agent predicted to have low EPS liability. Tiospirone possesses potent in vitro interactions at the serotonin 5-HT.sub.1A and 5-HT.sub.2 receptors as well as at the sigma and alpha -adrenergic receptor sites. It also demonstrates appreciable in vitro affinity for dopamine D.sub.2 receptors (a standard test predictive of neuroleptic activity) but does not cause dopamine receptor supersensitivity following chronic administration. ##STR3##
Specifically, tiospirone (i) is an azaspirodecanedione bridged by a tetramethylene chain to a benzisothiazolyl piperazine. Its chemical name is 8-[4-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]butyl]-8azaspiro[4.5]de cane-7,9-dione. Such heterocyclic carbon 4.5]decane-7,9-dione. Such heterocyclic carbon compounds having drug and bio-affecting properties are set forth in U.S. Pat. No. 4,411,901 (Temple, Jr. et al.), issued Oct. 25, 1983.
The Temple, et al., patent discloses N,N-disubstituted piperazinyl derivatives, wherein one substituent is benzisothiazol-3-yl or benzisoxazol-3-yl and the other is alkylene attached to heterocycles such as azaspiro[4.5]decanedione, dialkylglutarimide, thiazolidinedione and spirocyclopentylthiazolidinedione or butyrophenone-like groups. A preferred compound having antipsychotic activity is 8-[4-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]butyl]-8-azaspiro[4.5]deca ne-7,9-dione, i.e. tiospirone (i).
The compounds disclosed in the I.emple, et al. patent are useful pharmacological agents with psychotropic properties. In this regard, they typically exhibit selective central nervous system (CNS) activity at nontoxic doses and are of particular interest as neuroleptic (antipsychotic) agents. As with other known antipsychotics, the tiospirone compound evokes certain responses in standard in vivo and in vitro pharmacological test systems which are known to correlate well with relief of anxiety and symptoms of acute and chronic psychosis in man.
Studies into the metabolism and pharmacokinetics (MAP) of tiospirone have identified novel oxygenated derivatives of the tiospirone molecule which possess biological activities similar to the parent molecule. One such oxygenated derivative of tiospirone is set forth in U.S. Pat. No. 4,656,173 (Yevich, et al.), issued Apr. 7, 1987. This oxygenated tiospirone compound (ii) has the general formula 8-[4-[4-(1-oxo-l,2-benzisothiazol-3-yl) -1-piperazinyl]butyl]-8-azaspiro[4.5]decane-7,9-dione. ##STR4##
It is noteworthy that the attenuation of in vitro binding affinity observed for this compound compared to tiospirone did not affect its potency in in vivo screens predictive of antipsychotic activity (See Tables 6 and 7). Metabolic interconversion between the sulfur-oxide (ii) and tiospirone (i) has been proposed thus categorizing the sulfoxide as a prodrug form of the parent drug. This principle is further discussed in the Yevich, et al. patent, incorporated herein by reference.
The aforementioned MAP studies also identified metabolites where metabolic oxygenation occurred at various carbon atoms about the molecule. Metabolic rearrangement of the compound produced by hydroxylation at C-6 of the azaspirodecanedione portion of the molecule has been observed to produce an oxaspirononanone heterocycle. Therefore, the present invention also includes the rearranged metabolites of tiospirone such that a preferred group of compounds have the general Formula (II): ##STR5##
wherein X is selected from the group consisting of S, SO and SO.sub.2; and pharmaceutically acceptable acid addition salts and solvates thereof.
Preparation of the aforementioned entities require the synthesis of necessary, novel precursors to the compounds of the present invention. Subsequently, the present invention also includes novel substituted derivatives of the benzisothiazole-piperazine moiety such that a preferred group of compounds have the general Formula (III): ##STR6##
wherein R.sup.4 is selected from the group consisting of hydrogen, methyl and oxo; X is selected from the group consisting of S, SO, and SO.sub.2; and Z is either hydrogen or lower (C ) alkyloxycarbonyl, with the proviso that R.sup.4 and Z cannot both be hydrogen when X is S or S02, and the solid and dotted lines refer to either a double covalent bond or a single covalent bond with another hydrogen atom covalently bonded to the carbon terminus end; and the pharmaceutically acceptable acid addition salts and solvates thereof.
Compounds related to those of Formula III having antiinflammatory properties are set forth in U.S. Pat. No. 4,104,388 (Wade, et al.) issued Aug. 1, 1978. The Wade, et al. patent discloses 3-substituted benzisothiazole 1,1-dioxides. While these antiinflammatory compounds are generally related to the compounds of the instant invention, they are nonetheless structurally distinguishable mainly on the basis of substitution about the 3-piperazinyl moiety.
While the prior art compounds listed above are generally related to the compounds of the instant invention, they are nonetheless distinguishable thereof structurally on the basis that the compounds of the instant invention are (1) oxygenated at designated sites about the compound, (2) rearranged compounds, and/or (3) novel precursors of the aforementioned compounds. None of the aforementioned references disclose or suggest the specific metabolites or rearranged metabolites of the antipsychotic agent tiospirone as set forth in the present invention. Furthermore, additional advantages of the present invention shall become apparent as described below.